rs1114167806

chr2-47463095-TAATG-Tchr2-47463095-TAATG-TAATGAATG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):c.1457_1460del(p.Asn486ThrfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 8.76

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47463095-TAATG-T is Pathogenic according to our data. Variant chr2-47463095-TAATG-T is described in ClinVar as [Pathogenic]. Clinvar id is 90670.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47463095-TAATG-T is described in Lovd as [Likely_pathogenic]. Variant chr2-47463095-TAATG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1457_1460del	p.Asn486ThrfsTer10	frameshift_variant	9/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1457_1460del	p.Asn486ThrfsTer10	frameshift_variant	9/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 30, 2020	This variant deletes 4 nucleotides in exon 9 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch Syndrome (PMID: 10413423, 12386821, 15042510, 25782445, 28874130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2024	The c.1457_1460delATGA pathogenic mutation, located in coding exon 9 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1457 to 1460, causing a translational frameshift with a predicted alternate stop codon (p.N486Tfs*10). This alteration has also been reported in multiple individuals with personal and/or family history consistent with Lynch syndrome and is described in the literature as a Chinese founder mutation (Chan TL et al, J. Natl. Cancer Inst. 1999 Jul; 91(14):1221-6; Yuen ST et al, Oncogene 2002 Oct; 21(49):7585-92; Chan TL et al, Am. J. Hum. Genet. 2004 May; 74(5):1035-42; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Cruz-Correa M et al. Fam Cancer, 2015 Sep;14:415-25; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27(5):795-800; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). Additionally, this alteration was identified in multiple patients with breast and/or ovarian cancer (Kwong A et al. J Mol Diagn, 2020 04;22:544-554). Of note, this alteration is also designated as c.1452_1455delAATG and c.1457del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Lynch syndrome 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 02, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Carcinoma of colon Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH2 p.Asn486ThrfsX10 variant was identified in 9 of 598 proband chromosomes (frequency: 0.015) from Asian individuals or families with colorectal cancer (Chan 1999, Chan 2004, Yuen 2002), and was not identified in 210 control chromosomes from healthy individuals (Chan 1999).The variant was also identified in dbSNP (ID: rs63750148), HGMD, “InSiGHT Colon Cancer Database” and the ClinVar database (classified as a pathogenic variant). The p.Asn486ThrfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 486 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. Two studies have suggested that p.Asn486ThrfsX10 variant is a founder mutation and is common in the southern Chinese population (Chan 2004, Yuen 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3DMed Clinical Laboratory Inc	Aug 03, 2017	- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation introducing premature termination codon -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25345868, 24710284, 15516845, 12386821, 24307375, 26787237, 15042510, 10413423, 32068069, 28874130, 28449805, 30730459, 31830689, 30521064, 28445943) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change creates a premature translational stop signal (p.Asn486Thrfs*10) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch Syndrome (PMID: 10413423, 28449805, 28874130). This variant is also known as c.1452_1455delAATG. ClinVar contains an entry for this variant (Variation ID: 90670). For these reasons, this variant has been classified as Pathogenic. -

Colon cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1114167806; hg19: chr2-47690234;